AAV-mediated Stambp gene replacement therapy rescues neurological defects in a mouse model of microcephaly-capillary malformation syndrome.

The microcephaly-capillary malformation (MIC-CAP) syndrome is a life-threatening disease caused by biallelic mutations of the STAMBP gene, which encodes an endosomal deubiquitinating enzyme. To establish a suitable preclinical animal model for clinical therapeutic practice, we generated a central nervous system (CNS)-specific Stambp knockout mouse model (Stambp ^Sox1-cKO) that phenocopies Stambp null mice including progressive microcephaly, postnatal growth retardation and complete penetrance of preweaning death. In this MIC-CAP syndrome mouse model, early-onset neuronal death occurs specifically in the hippocampus and cortex, accompanied by aggregation of ubiquitinated proteins, and massive neuroinflammation. Importantly, neonatal AAV9-mediated gene supplementation of Stambp in the brain could significantly improve neurological defects, sustain growth, and prolong the lifespan of Stambp^Sox1-cKO mice. Together, our findings reveal a central role of brain defects in the pathogenesis of STAMBP deficiency and provide preclinical evidence that postnatal gene replacement is an effective approach to cure the disease.